Somatic gene therapy of bone marrow and peripheral blood stem cells has been proposed as an alternative to conventional AIDS therapies. Successful inhibition of HIV replication with ribozymes, antisense oligonucleotides, RNA-decoys and transdominant mutants has been reported. We have applied a new technology, Genetic Suppressor Element (GSE) Technology, to isolate efficient inhibitors of the HIV life cycle. The Phase I study resulted in the isolation of multiple elements capable of interfering with the induction of latency. Two elements showed significant effect against challenge with different HIV isolates and appeared to be more potent than a rationally designed transdominant mutant, RevMl0. In Phase II, we will evaluate the anti-HIV potency of the isolated elements in both latent and productive models, optimize expression of the elements and design new vectors containing the most efficient combinations of elements. The protective effect of these elements will be tested in human T-Iymphocytes from normal and HIV infected donors in a preclinical setting. GSE expressing human CD4+ T- lymphocytes will also be tested for their effect on immunocompetence. Phase II is aimed at the identification of potent and nontoxic GSEs that will be used in clinical trials directed at making hematopoietic stem cells resistant to HIV infection. PROPOSED COMMERCIAL APPLICATION: This Phase II study will result in the identification of the most potent anti-HIV Genetic Suppressor Elements (GSEs) and their combinations, that will be used in gene therapy of AIDS. These elements will identify new targets for rational drug design.